Androgen receptor phosphorylation at serine 81 and serine 213 in castrate-resistant prostate cancer

McAllister, M. J., McCall, P., Dickson, A., Underwood, M. A., Andersen, D., Holmes, E., Market, E., Leung, H. Y. and Edwards, J. (2020) Androgen receptor phosphorylation at serine 81 and serine 213 in castrate-resistant prostate cancer. Prostate Cancer and Prostatic Diseases, (doi: 10.1038/s41391-020-0235-1) (PMID:32358577) (Early Online Publication)

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Abstract

Background: Despite increases in diagnostics and effective treatments, over 300,000 men die from prostate cancer highlighting the need for specific and differentiating biomarkers. AR phosphorylation associates with castrate-resistance, with pARser213 promoting transcriptional activity. We hypothesise that combined pARser81 and pARser213 reduces survival and would benefit from dual-targeting androgen-dependent and Akt-driven disease. Methods: Immunohistochemistry and immunofluorescence were performed on matched hormone-naive and castrate-resistant prostate cancer samples. TempO-Seq gene profiling was analysed using DESeq2 package. LNCaP-AI cells were stimulated with DHT or EGF. WST-1 assays were performed to determine effects of Enzalutamide and BKM120 on cell viability. Results: Following the development of castrate-resistance, pARser81 expression reduced and pARser213 expression increased. Castrate-resistance pARser81 expression was not associated with survival but high pARser213 expression was associated with reduced survival from relapse. Combined high pARser81 and pARser213 was associated with reduced survival from relapse. pARser81 expression was induced by 10 nM DHT or 10 nM EGF and pARser213 expression was induced by treatment with 10 nM EGF in LNCaP-AI cells. Cell viability was reduced following treatment with 10 nM Enzalutamide and 10 nM BKM120. Eight genes were differentially expressed between hormone-naive and castrate-resistant tumours and twenty-five genes were differentially expressed between castrate-resistant tumours with high and low pARser213 expression. Conclusion: Combined pARser81 and pARser213 provides a novel prognostic biomarker for castrate-resistant disease and a potential predictive and therapeutic target for prostate cancer. Further studies will be required to investigate the combined effects of targeting AR and PI3K/AKT signalling.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Edwards, Professor Joanne and Underwood, Mr Mark and Dickson, Ms Ashley and Leung, Professor Hing and McAllister, Milly and McCall, Dr Pamela
Authors: McAllister, M. J., McCall, P., Dickson, A., Underwood, M. A., Andersen, D., Holmes, E., Market, E., Leung, H. Y., and Edwards, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Prostate Cancer and Prostatic Diseases
Publisher:Nature Research
ISSN:1365-7852
ISSN (Online):1476-5608
Published Online:01 May 2020
Copyright Holders:Copyright © 2020 Springer Nature Limited
First Published:First published in Prostate Cancer and Prostatic Diseases 2020
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171308Identification of biomarkers to predict response to synergistic targeting of AR and PI3K pathway in castrate resistant prostate cancer.Joanne EdwardsProstate Cancer UK (PROSCANU)S14-003CS - Experimental Therapeutics